Sex-related differences in outcome of thoracic aortic surgery

Background Sex-related dissimilarities’ influence on outcomes following thoracic aortic surgery is poorly understood. Our aim is to examine sex-related disparities in patients undergoing thoracic aortic aneurysm (TAA). Methods A total of 455 cases undergoing thoracic aortic aneurysm (TAA) surgery were consecutively enrolled between December 2009 and December 2015 in a Chinese hospital. Primary outcomes, including overall mortality and related risk factors, were evaluated. Cox regression is utilized to recognize the independent risk factor of these consequences. Results Females, compared to males, had greater indexed aortic diameters and higher aortic transvalvular pressure differences. For the location of aortic aneurysms, females had a higher rate of aortic arch involvement, while males had a higher rate of root involvement. Females underwent less frequent complex proximal aortic operations compared with males (29.5% versus 46.9%; p < 0.001). Women and men both had a lower rate of aortic transvalvular pressure difference and LV volume index 7 days after thoracic aortic surgery. The overall mortality for the women’s groups (11%) was suggestively greater compared to 4.9% for the men’s groups (p = 0.026). Renal failure and aortic arch involvement were the main risk factors associated with males’ survival, while maximum indexed aortic diameter and cross-clamp time were the risk factors associated with females’ survival. Conclusions The outcome after TAA surgery was less favorable in women with significantly increased overall mortality. It highlights the need to focus on implementing personalized surgery strategies and gender-specific guidelines in treating female patients following TAA surgery.


Background
Women and men have discrepancies in the occurrence, therapy, and outcome of cardiovascular illness [1].In recent years, gender-related dissimilarities have been determined in patients undergoing a variety of surgeries, including coronary surgery, mitral valve surgery, coronary surgery, united valve, and ruptured abdominal aortic aneurysm surgery [2].As a common serious disease, thoracic aortic aneurysm (TAA) requires surgical intervention because of the threat of dissection or rupture [3].The surgical treatment of a TAA is frequently performed in the world.The aorta can be repaired endovascularly or replaced by a synthetic tube (graft) in the thorax or by open surgery (TEVAR) [4], here TEVAR standed for thoracic endovascular aortic repair, which was a minimally invasive procedure used to treat thoracic aortic aneurysms.While brain/or heart damage derived from a variety of factors such as atheromatous or calcium plaques, reduced circulatory blood flow, long circulatory arrest time, and cardiac dysfunction [5,6] are very common during or after surgery.To date, TAA surgery has a mortality rate up to 10% [7].There is a need to improve the perioperative outcomes of patients undergoing TAA surgery [8].A personalized approach to patients undergoing TAA surgery may prove to be an effective policy to improve total outcomes.
Given the physiological, genetic, behavioral, and psychological dissimilarities between women and men, there is the possibility of differences in surgical outcomes.We conducted this study to investigate gender dissilimarities in patients undergoing TAA surgery and assess the sexrelated differences in clinical outcomes.

Study population
Between December 2009 and December 2015, patients (n = 455) with thoracic aortic aneurysms undergoing thoracic aortic surgery were retrospectively enrolled at the Department of Cardiovascular Surgery of Changhai Hospital (Shanghai, China).Inclusion criteria of patients undergoing TAA surgery (median sternotomy) include total arch reconstructions, hemiarch replacements, descending thoracic aortic repairs, and distal arch.Thoracic-abdominal aortic repair cases requiring circulatory arrest or cases not requiring aortic repairs such as congenital conditions and tumor excision, and emerging cases were excluded from this study.The medical records of the patients, including demographics, clinical findings, the sex difference in the outcome, and follow-up, were collected.The Institutional Review Committee approved this research and all informed contents were obtained.

Outcome measure
The primary outcomes for evaluation included locations of thoracic aortic aneurysms, baseline Characteristics of patients before surgery and 7 days after thoracic aortic surgery, in-hospital mortality, overall mortality, and major morbidity and risk factors for overall mortality.

Statistical methods
Categorical data were expressed as a percentage (%), and continuous variables were expressed as mean ± standard deviation.Student t-test was utilized for comparing continuous variables.The nominal variable was compared using Chi-square or Fisher's exact tests.Cox regression was used to describe appropriate risk factors for overall death.A p-value of fewer than 0.05 (two-tailed) was considered statistically significant.Statistical analysis was executed by SPSS 21.0 software (Chicago, SPSS, IL).
Other medical histories, including the incidence of hypertension (P = 0.656), diabetes mellitus (P = 0.192), dyslipidemia (P = 1.000), and renal insufficiency (P = 0.513) were not different between the two groups.Anatomically, female patients had a smaller body surface region (P < 0.001), translating into higher indexed aortic diameters (P = 0.001).For valve anatomy, both male and female patients had a similar proportion of bicuspid aortic valve (P = 0.250) and aortic valve stenosis (P = 0.089), whereas female patients had a higher aortic valve transvalvular pressure difference (P = 0.036), and male patients had a superior ratio of aortic valve insufficiency (P < 0.001).The differences in baseline characteristics between women and men were summarized in Table 1.
Moreover, there were significant differences in terms of the proportion of the location of aortic aneurysms, including aortic root, aortic arch, ascending aorta, and aortic root between female and male patients (see Table 2).In brief, Female patients had a higher rate of arch involvement (P = 0.005), whereas the male group had a greater rate of root involvement (P = 0.003).In addition, male patients had a higher proportion of aortic aneurysms involving ascending aorta and aortic root (P = 0.001) and arch or/and descending aortic involvement (P = 0.034) compared to female patients (see Table 2).

Operative features
Female patients experienced fewer frequent multifaceted proximal aortic operations, including the Bentall procedure (26% versus 40.5%;P = 0.003).The rate of the procedure of arch replacement, including Hemiarch replacement (P = 0.092), overall arch replacement (P = 0.115), and elephant trunk repair (P = 1.000), was similar between the two groups, as was the rate of concomitant surgeries (32.2% versus 36.5%;P = 0.361).There was no significant dissimilarity in the cardiopulmonary bypass periods (P = 0.362), cross-clamp times (P = 0.367), and circulatory arrest periods (P = 0.068).Female patients had a higher intraoperative transfusion rate (78.1% versus 61.5%; P < 0.001), and this was driven by the utilization of fresh frozen plasma and packed red blood cells (see Table 3).

Primary outcomes
There was no significant dissimilarity in the mean follow-up time among women and men groups (men: 49.4 ± 14.33 mts versus Women: 49.4 ± 14.70 mts; p = 0.956).The overall mortality rate in the women's  groups (11.0%) was higher compared to 4.9% in the men's groups (p = 0.026), as demonstrated in Table 5.The actuarial survival rate was expressively higher in male patients compared to female patients (95.1% versus 89.0% at 5 years).Neurological complications (p = 1.000), need for re-operation (p = 0.654), prolonged ventilation time (p = 0.204), dialysis-dependent renal failure (p = 1.000),ICU days (p = 0.229) and overall hospital stay (p = 0.685) were not different between two groups (Table 5).Lastly, we conducted a univariate cox regression analysis of sex-specific risk factors associated with overall mortality.For male patients, several risk factors were identified, including renal failure (HR = 21.794,p<0.001), aortic arch contribution (HR = 13.749,p<0.001), and arch or/and descending aortic involvement (HR = 26.746,p<0.001), which had a positive impact on survival.Other risk factors that negatively influenced survival were maximum indexed aortic diameter, maximum aortic diameter, ICU stays, overall hospital stay, cardiopulmonary bypass, cross-clamp time, and circulatory arrest period.Preoperative aortic valve inadequacy positively influenced survival (HR = 0.349, p = 0.027) (Table 6).For female patients, NYHA I state and NYHA II had a positive impact on survival (HR = 0.068, p = 0.021 and HR = 0.082, p = 0.043, respectively), suggesting comparatively better clinical prognosis at the time of operation.In addition, maximum indexed aortic diameter and Cross clamp time were identified as risk factors associated with survival, suggesting that these patients had a higher comorbidity rate (Table 6).

Discussion
Gender-related dissimilarities have been identified across a variety of valve, coronary, and aortic aneurysm surgeries.Thoracic aortic aneurysm (TAA) surgery remains an area where overall post-operative outcomes may be considerably improved.Complex TAA surgeries, especially hypothermic circulatory arrest (HCA), are at greater risk of surgical procedure.As such, surgical outcomes might benefit from a more individualized approach.Given the physiological and psychological differences between female and male patients, sex-related differences may exist in patients undergoing thoracic aortic surgery.In this study, we observed that women undergoing TAA surgery have a higher overall mortality rate, thus supporting gender-related differences in patients after thoracic aortic surgery.
The results of Cox regression analysis indicated that maximum indexed aortic diameter was a female-specific risk factor for overall mortality.Despite the complete diameters of the aorta being superior in men compared to women, female patients exhibited a greater diameter/ BSA ratio in this study.This result was consistent with the previous study that women with smaller aorta diameters had faster disease progression because the absolute diameter was nearly equal.It suggests that the diameter of the aorta and the rate of its progression could predict the severity of the aortic diseases and thus play an important role in the formation of aortic aneurysms.Assessing sex-specific correlates of aneurysm size is important to understand and monitor the processes of poorer TAA outcomes in women as bigger aneurysms are at risk of acute aortic syndrome and are the driver of therapeutic choices [9].These results imply differences in the mechanical pathology between women and men.It is supported by the evidence that women presented increased expression of matrix metalloproteinase 2 and 9 and decreased expression of metalloproteinase inhibitor 1 and 2 in tissues in aneurysmal disease, thus leading to increased extracellular matrix destruction in women, further resulting in greater aortic wall stiffness and pulsatile arterial load [10].In addition, sex hormones were also reported to affect the different outcomes of abdominal aortic aneurysms.As a result, we hypothesized that a mechanical influence presented on the thoracic aortic aneurysms as indicated by another study [11].Despite TAA being more predominant in men, women have a higher mortality rate as shown in aortic diseases [12], quicker aneurysm development, and greater dissection  Additionally, both female and male patients had a lower rate of aortic valve transvalvular pressure difference and LV volume index in the early 7 days after thoracic aortic surgery, indicating the early effective treatment of the TAA surgery as shown in another study [18].There was no significant difference in the ventricular function and interventricular septal thickness between pre-operation and post-operation (i.e. the early 7 days after surgery) groups undergoing TAAs, regardless of their gender identity which is consistent with the previous study [19].Interestingly, preoperative aortic valve insufficiency was identified as a risk factor positively associated with survival in the male group undergoing TAAs [13][14][15].In contrast, NYHA I or class II status was determined as a risk factor positively associated with survival in the female group undergoing TAAs which had been shown in mitral valve surgery [20].These results implied that the clinical outcomes of TAA surgery were correlated with surgical timing in patients undergoing TAA surgery.In general, women receive less ideal medical and surgical treatment for diseases such as coronary artery disease, ruptured abdominal aortic aneurysms, and mitral valve disease [21].Moreover, aortic surgery was typically implemented on females later in the illness progression -a contemporary technical problem because of smaller body size and tissue instability in women [22].All these factors may explain worse outcomes of TAA surgery -a higher mortality rate, in female patients in comparison to male patients in the current study.Thus, more perioperative attention/care and early TAA treatment would effectively reduce the disparity of outcomes between female and male patients undergoing TAA surgery as shown in abdominal aortic aneurysm repair surgery [23].Current guidelines are often revised through risk factor analysis, tending to decrease cut-off values for thoracic aortic surgery to 5 cm and to decrease the cut-off value for specific risk groups to 4.5 cm, such as Marfan syndrome [24].

Limitations
There are several limitations to the current study that should be acknowledged.First, this research has been conducted at a single center, and the outcomes can not reflect practices or technologies utilized at other institutions.Second, the study was limited by its retrospective nature.Third, this study did not assess several factors such as perioperative care and drug use that may be related to gender-related outcomes.Finally, the provided samples (455 cases) in the study did not enough support the need for more statistical analysis to assess the mortality rates of different surgical approaches between male and female in TAA surgery.The subgroup analysis with the insufficient sample size would make false negative reports, therefore we abandoned subgroup analysis of different surgical approaches.Thereafter our findings would be verified in several large-scale multicenter studies.

Conclusions
Female patients presenting with TAAs have a higher overall mortality rate and aortic diameter is associated with worse outcomes of TAA surgery.Our findings highlight sex-related differences in patients undergoing TAA surgery and thus promote the development of a personalized approach to TAA surgery with respect to sex.

Table 1
Baseline characteristics LVEF: left ventricular ejection fraction.A p value < 0.05 was considered statistically significantt

Table 2
Location differences of thoracic aortic aneurysms between female and male patients

Table 3
Intraoperative differences between female and male patients ASD: atrial septal defect; VSD: ventricular septal defect; PRBC, FFP, packed red blood cells; fresh frozen plasma.A p value < 0.05 was considered statistically significant

Table 4
Comparison between baseline characteristics of patients and 7-day outcomes after thoracic aortic surgery a: transvalvular pressure difference; b: LV volume index at end-diastole (ml/m2.7);c: IVST at end-diastole (mm); d: LV PWT at end-diastole (mm).A p value < 0.05 was considered statistically significant

Table 5
Outcome Differences Between female and male patients after thoracic aortic surgery